title: ALK as a paradigm of oncogenic promiscuity: different mechanisms of activation and different fusion partners drive tumors of different lineages.
abstract: Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase protein implicated in a variety of hematological malignancies and solid tumors. Since the identification of the ALK gene in 1994 as the target of the t(2;5) chromosomal translocation in anaplastic large cell lymphoma, ALK has been proven a remarkably promiscuous oncogene. ALK contributes to the development of a notable assortment of tumor types from different lineages, including hematolymphoid, mesenchymal, epithelial and neural tumors, through a variety of genetic mechanisms: gene fusions, activating point mutations, and gene amplification. Recent developments led to significant diagnostic and therapeutic advances, including efficient diagnostic tests and ALK-targeting agents readily available in the clinical setting. This review addresses some therapeutic considerations of ALK-targeted agents and the biologic implications of ALK oncogenic promiscuity, but the main points discussed are: 1) the variety of mechanisms that result in activation of the ALK oncogene, with emphasis on the promiscuous partnerships demonstrated in chromosomal rearrangements; 2) the diversity of tumor types of different lineages in which ALK has been implicated as a pathogenic driver; and 3) the different diagnostic tests available to identify ALK-driven tumors, and their respective indications.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Adrian
authors.initials: A
authors.lastname: Mariño-Enríquez
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA; Center for Advanced Molecular Diagnostics, Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA. Electronic address: pdalcin@partners.org.
authors.forename: Paola
authors.initials: P
authors.lastname: Dal Cin
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D019070:Cell Lineage; D005784:Gene Amplification; D006801:Humans; D017728:Lymphoma, Large-Cell, Anaplastic / Q000201:enzymology / Q000235:genetics; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D009857:Oncogenes; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D014178:Translocation, Genetic
chemical_list: D015514:Oncogene Proteins, Fusion; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
keywords: ALK; fusion proteins; oncogene; receptor tyrosine kinase; translocations